Cancer progression is driven not only by genetic mutations but also by epigenetic changes that determine how the genome is organized and regulated. In colorectal cancer, metastasis is the leading cause of death, yet it often arises without new point mutations, leaving a major gap in understanding how tumors acquire metastatic and drug-resistant traits. This ASPIRE Award project addresses the overarching question of whether chromosomal instability, characterized by large-scale structural alterations, reshapes the cancer epigenome in ways that promote phenotypic plasticity and metastatic behavior. Clarifying this relationship is critical, as chromosomal instability is nearly universal in advanced disease and may represent a previously unrecognized driver of lethal cancer progression.
The research team will integrate two cutting-edge, complementary technologies to directly map how structural alterations influence chromatin accessibility, three-dimensional genome organization, and DNA methylation in metastatic colorectal cancer. By applying single-cell dATAC and long-read Pore-C to clinically annotated primary and metastatic tumor samples, they will reconstruct altered cancer genomes while simultaneously measuring their regulatory states. This integrative framework is expected to reveal how structural genome changes reprogram epigenetic landscapes and generate new cellular states linked to metastasis and therapy resistance. The findings could lay the groundwork for biomarkers and therapeutic strategies that better predict and counter aggressive cancer behavior, ultimately improving outcomes for patients with advanced colorectal cancer.